The immunogenicity of colorectal cancers with high-degree microsatellite instability

BACKGROUND: High-degree microsatellite instability (MSI-H) is a feature of approximately 15% of sporadic colorectal cancers. Patients with MSI-H cancers have been reported to have a better prognosis than those with non-MSI-H cancers. The MSI-H subset is also characterised by a dense infiltrate of intra-epithelial lymphocytes and the hypothesis that the latter represents an efficacious immune response contributing to improved outcome is very attractive. METHODS: Data for this review were identified by searches of MEDLINE, PubMed, and cross references from relevant articles using the search terms 'microsatellite instability', 'colorectal cancer' and 'immunology', 'immune response' or 'immunogenicity'. RESULTS: A total of 38 articles were identified by the search criteria and a further 95 articles by cross-referencing. The relevance of the articles to be interviewed was established by hand searching. Out of a total of 133 articles identified, 47 articles were rejected due to lack of relevance. A total of 86 articles were included in the review, pertaining to microsatellite instability in colorectal cancer, and immune mechanisms in colorectal cancer. CONCLUSION: It is suggested that this distinct group of colorectal cancers may have inherent immunogenic properties and that further elucidation of these may be invaluable to the development of successful immunotherapy

Colorectal cancers with microsatellite instability display mRNA expression signatures characteristic of increased immunogenicity

BACKGROUND: Colorectal cancers displaying high-degree microsatellite instability (MSI-H) have an improved prognosis compared to microsatellite stable (MSS) cancers. The observation of pronounced lymphocytic infiltrates suggests that MSI-H cancers are inherently more immunogenic. We aimed to compare the gene expression profiles of MSI-H and MSS cancers to provide evidence for an activated immune response in the former. RESULTS: We analysed tissue from 133 colorectal cancer patients with full consent and Local Ethics Committee approval. Genomic DNA was analysed for microsatellite instability in BAT-26. High-quality RNA was used for microarray analysis on the Affymetrix(® )HG-U133A chip. Data was analysed on GeneSpring software version 6.0. Confirmatory real-time RT-PCR was performed on 28 MSI-H and 26 MSS cancers. A comparison of 29 MSI-H and 104 MSS cancers identified 2070 genes that were differentially expressed between the two groups [P < 0.005]. Significantly, many key immunomodulatory genes were up-regulated in MSI-H cancers. These included antigen chaperone molecules (HSP-70, HSP-110, Calreticulin, gp96), pro-inflammatory cytokines (Interleukin (IL)-18, IL-15, IL-8, IL-24, IL-7) and cytotoxic mediators (Granulysin, Granzyme A). Quantitative RT-PCR confirmed up-regulation of HSP-70 [P = 0.016], HSP-110 [P = 0.002], IL-18 [P = 0.004], IL-8 [0.002] and Granulysin [P < 0.0001]. CONCLUSIONS: The upregulation of a large number of genes implicated in immune response supports the theory that MSI-H cancers are immunogenic. The novel observation of Heat Shock Protein up-regulation in MSI-H cancer is highly significant in light of the recognised roles of these proteins in innate and antigen-specific immunogenicity. Increased mRNA levels of pro-inflammatory cytokines and cytotoxic mediators also indicate an activated anti-tumour immune response

Sociodemographic Variations in the Uptake of Faecal Immunochemical Tests in Primary Care

Background: Faecal Immunochemical Testing (FIT) usage for symptomatic patients is increasing, but variations in use by sociodemographics are unknown. We introduced FIT for symptomatic patients in November 2017. Aim: Identify whether demographics, ethnicity or social deprivation affect FIT return in symptomatic patients. Design and Setting: FIT was introduced as a triage tool in Primary Care and was mandated for all colorectal referrals (except rectal bleeding/mass) to secondary care. FIT was used, alongside full blood count and ferritin, to stratify colorectal cancer risk. Method: All referrals November 2017-December 2021 were retrospectively reviewed. Sociodemographic factors affecting FIT return were analysed by multivariate logistic regression. Results: 35,289 patients returned their index FIT (90.7%), 3631 (9.3%) did not. On multivariate analysis, males were less likely to return FIT (OR 1.11, 95%CI 1.03-1.19). Patients over 65 were more likely to return FIT (OR 0.78 for non-return, 95%CI 0.72-0.83). Unreturned FIT was more than doubled in the most compared to the least deprived (OR 2.20, 95%CI 1.99-2.43). Patients from Asian (OR 1.82, 95%CI 1.58-2.10), Black (OR 1.21, 95%CI 0.98-1.49) and Mixed/Other ethnic groups (OR 1.29, 95%CI 1.05-1.59) were more likely to not return FIT compared to White ethnicity. 599 colorectal cancers were detected (1.5%), 561 in those who returned a first FIT request, 38 in those who did not. Conclusion: FIT return in those suspected of having colorectal cancer varies by gender, age, ethnicity, and socioeconomic deprivation. Strategies to mitigate effects on FIT return and colorectal cancer detection should be considered as FIT usage expands

Faecal immunochemical testing and blood tests for prioritization of urgent colorectal cancer referrals in symptomatic patients: a 2-year evaluation

BackgroundA novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation.MethodsThe RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses.ResultsIn 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4–9.9 µg Hb/g in 1583 (11.8 per cent), 10–99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4–9.9 µg Hb/g faeces, 3.3 per cent for fHb 10–99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10–19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent.ConclusionUse of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification

Choice of faecal immunochemical test matters: Comparison of OC-Sensor and HM-JACKarc, in the assessment of patients at high risk of colorectal cancer

Objectives: Currently NICE recommends the use of faecal immunochemical test (FIT) at faecal haemoglobin concentrations (f-Hb) of 10 μg Hb/g faeces to stratify for colorectal cancer (CRC) risk in symptomatic populations. This f-Hb cut-off is advised across all analysers, despite the fact that a direct comparison of analyser performance, in a clinical setting, has not been performed.Methods: Two specimen collection devices (OC-Sensor, OC-S; HM-JACKarc, HM-J) were sent to 914 consecutive individuals referred for follow up due to their increased risk of CRC. Agreement of f-Hb around cut-offs of 4, 10 and 150 µg Hb/g faeces and CRC detection rates were assessed. Two OC-S devices were sent to a further 114 individuals, for within test comparisons.Results: 732 (80.1%) individuals correctly completed and returned two different FIT devices, with 38 (5.2%) CRCs detected. Median f-Hb for individuals diagnosed with and without CRC were 258.5 and 1.8 µg Hb/g faeces for OC-S and 318.1 and 1.0 µg Hb/g faeces for HM-J respectively.Correlation of f-Hb results between OC-S/HM-J over the full range was rho=0.74, p[less than]0.001. Using a f-Hb of 4μg Hb/g faeces for both tests found an agreement of 88.1%, at 10μg Hb/g faeces 91.7% and at 150μg Hb/g faeces 96.3%.114 individuals completed and returned two OC-S devices; correlation across the full range was rho=0.98, p[less than]0.001.Conclusion: We found large variations in f-Hb when different FIT devices were used, but a smaller variation when the same FIT device was used. Our data suggest that analyser-specific f-Hb cut-offs are applied with regard to clinical decision making, especially at lower f-Hb

Long term health related quality of life following colorectal cancer surgery: patient reported outcomes in a remote follow-up population

Background: Remote follow-up (RFU) after colorectal cancer (CRC) surgery allows delivery of surveillance tests without the need for regular outpatient clinical appointments. However, little is known about health related quality of life (HRQoL) in RFU patients.Methods: EQ-5D, QLQ-C30 and QLQ-C29 questionnaires were distributed to CRC patients enrolled in a RFU programme. The primary outcome of HRQoL scores was analysed by year of RFU, demographics, operation-type, stoma and adherence to RFU protocols. Results:428 respondents (59.3%), mean age of 71years(SD 10.1) and a median RFU time of 2.6years (IQR: 1.6-4.8 years) were included. 26.6% of patients reported ‘perfect health’. The median EQ-5D index score was 0.785 (IQR: 0.671-1) and QLQ-C30 Global HRQoL score was 75 (IQR: 58.3-83.3). Females had significantly lower EQ-5D median score of 0.767 (IQR: 0.666-0.879, p=0.0088). Lower QLQ-C30 HRQoL scores were seen in stoma patients, median 66.6 (IQR: 58.3-83.3, p=0.0029). Erectile dysfunction (p=0.0006) and poor body image (p=0.001) were also reported more frequently in stoma patients. Patients undergoing right-sided resection reported a lower median EQ-5D score of 0.765 (IQR: 0.666-0.879, p=0.028) and higher pain severity (p=0.0367) compared with left-sided resections. There were 128 (29.4%) patients that breached RFU protocol and were seen in adhoc colorectal clinics. However, there was no statistical difference in HRQoL between patients who adhered to or breached RFU protocols.Conclusions: Overall HRQoL in patients in RFU is good, with no difference in those strictly followed up remotely. However, females, right-sided resections and patients with stomas may require additional clinical reviews.

Benign Ancient Schwannoma of the abdominal wall: An unwanted birthday present

<p>Abstract</p> <p>Background</p> <p>There has been a recent growth in the use of whole body Computerised Tomography (CT) scans in the private sector as a screening test for asymptomatic disease. This is despite scant evidence to show any positive effect on morbidity or mortality. There has been concern raised over the possible harms of the test in terms of radiation exposure as well as the risk and anxiety of further investigation and treatment for the large numbers of benign lesions identified.</p> <p>Case Presentation</p> <p>A healthy 64 year old lady received a privately funded whole body CT scan for her birthday which revealed an incidental mass in the right iliac fossa. This was investigated with further imaging and colonoscopy and as confident diagnosis could not be made, eventually excised. Histology demonstrated this to be a benign ancient schwannoma and we believe this to be the first reported case of an abdominal wall schwannoma in the English literature</p> <p>Conclusions</p> <p>Ancient schwannomas are rare tumours of the peripheral nerve sheaths more usually found in the head, neck and flexor surfaces of extremities. They are a subtype of classical schwannomas with a predominance of degenerative changes. Our case highlights the pitfalls of such screening tests in demonstrating benign disease and subjecting patients to what turns out to be unnecessary invasive investigation and treatment. It provides evidence as to the consequences of the large number of false positive results that are created by blind CT scanning of asymptomatic patients i.e. its tendency to detect pseudodiesease rather than affect survival rates. Should the number of scans increase there may be an unnecessary burden on NHS resources due to the large numbers of benign lesions picked up, that are then referred for further investigation.</p

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

BACKGROUND: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. METHODS: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. FINDINGS: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96-1·28). INTERPRETATION: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. FUNDING: National Institute for Health Research Health Services and Delivery Research Programme

Effectiveness of a national quality improvement programme to improve survival after emergency abdominal surgery (EPOCH): a stepped-wedge cluster-randomised trial

Background: Emergency abdominal surgery is associated with poor patient outcomes. We studied the effectiveness of a national quality improvement (QI) programme to implement a care pathway to improve survival for these patients. Methods: We did a stepped-wedge cluster-randomised trial of patients aged 40 years or older undergoing emergency open major abdominal surgery. Eligible UK National Health Service (NHS) hospitals (those that had an emergency general surgical service, a substantial volume of emergency abdominal surgery cases, and contributed data to the National Emergency Laparotomy Audit) were organised into 15 geographical clusters and commenced the QI programme in a random order, based on a computer-generated random sequence, over an 85-week period with one geographical cluster commencing the intervention every 5 weeks from the second to the 16th time period. Patients were masked to the study group, but it was not possible to mask hospital staff or investigators. The primary outcome measure was mortality within 90 days of surgery. Analyses were done on an intention-to-treat basis. This study is registered with the ISRCTN registry, number ISRCTN80682973. Findings: Treatment took place between March 3, 2014, and Oct 19, 2015. 22 754 patients were assessed for elegibility. Of 15 873 eligible patients from 93 NHS hospitals, primary outcome data were analysed for 8482 patients in the usual care group and 7374 in the QI group. Eight patients in the usual care group and nine patients in the QI group were not included in the analysis because of missing primary outcome data. The primary outcome of 90-day mortality occurred in 1210 (16%) patients in the QI group compared with 1393 (16%) patients in the usual care group (HR 1·11, 0·96–1·28). Interpretation: No survival benefit was observed from this QI programme to implement a care pathway for patients undergoing emergency abdominal surgery. Future QI programmes should ensure that teams have both the time and resources needed to improve patient care. Funding: National Institute for Health Research Health Services and Delivery Research Programme

The immunogenicity of microsatellite unstable colorectal cancers

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